title: Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin.
abstract: The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of β-catenin-T-cell factor (Tcf), a key mediator of canonical Wnt signaling, has been implicated in human colon cancer development. Current treatment of colon cancer depends on traditional cytotoxic agents with limited effects. Therefore, the identification of natural compounds that can disrupt the β-catenin-TcF complex to suppress cancer cell growth with fewer adverse side effects is needed. To identify compounds that inhibit the association between β-catenin and Tcf, we used computer docking to screen a natural compound library. Esculetin, also known as 6,7-dihydroxycoumarin, is a derivative of coumarin and was identified as a potential small-molecule inhibitor of the Wnt-β-catenin pathway. We then evaluated the effect of esculetin on the growth of various human colon cancer cell lines and its effect on Wnt-β-catenin signaling in cells and in an embryonic model. Esculetin disrupted the formation of the β-catenin-Tcf complex through direct binding with the Lys312, Gly307, Lys345, and Asn387 residues of β-catenin in colon cancer cells. In addition, esculetin effectively decreased viability and inhibited anchorage-independent growth of colon cancer cells. Esculetin potently antagonized the cellular effects of β-catenin-dependent activity, and in vivo treatment with esculetin suppressed tumor growth in a colon cancer xenograft mouse model. Our data indicate that the interaction between esculetin and β-catenin inhibits the formation of the β-catenin-Tcf complex, which could contribute to esculetin's positive therapeutic and preventive effects against colon carcinogenesis.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912. zgdong@hi.umn.edu.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Lim
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Aram
authors.initials: A
authors.lastname: Shin
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014468:Umbelliferones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D014982:Xenopus laevis; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D014468:Umbelliferones; D051176:beta Catenin; D008156:Luciferases; C007628:esculetin